IE51026B1 - Derivatives of 6beta-hydroxyalkylpenicillanic acids as beta-lactamase inhibitors - Google Patents

Abstract

6 beta -Hydroxymethyl-penicillanic acid sulfone and substituted a derivatives thereof, and their esters, of the formula: in which R1 is hydrogen or an ester- forming residue readily hydrolysable in vivo; R3 is hydrogen, sulpho, alkoxycarbonyl, alkanoyl, optionally substituted benzoyl; and R4 is hydrogen, alkyl, phenyl, pyridyl, benzyl or beta -phenethyl; are claimed as novel enhancers of the effectiveness of beta - lactam antibiotics against many beta - lactamase producing bacteria. The corresponding benzyl esters are also claimed as novel intermediates therefor.

Description

One of the most well-known and widely used class of antibacterial agents are the so-called β-lactam antibiotics. These compounds are characterized in that they have a nucleus consisting of a 2-azetidinone CB-lactam) ring fused to either a thiazolidine or a dihydro-1,3thiazine ring. When the nucleus contains a thiazolidine ring, the compounds are usually referred to generically as penicillins, whereas when the nucleus contains a dihydrothiazine ring, the compounds are referred to as cepha10 losporins. Typical examples of penicillins which are commonly used in clinical practice are benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), ampicillin and carbenicillin; typical examples of common cephalosporins are cephalothin, cephalexin and cefazolin.

However, despite the wide use and wide acceptance of the β-lactam antibiotics as valuable chemotherapeutic agents, they suffer from the major drawback that certain members are not active against certain microorganisms.

It is thought that in many instances this resistance of a particular microorganism to a given β-lactam antibiotic results because the microorganism produces a β-lactamase. The latter substances are enzymes which cleave the βlactam ring of penicillins and cephalosporins to give products which are devoid of antibacterial activity.

However, certain substances have the ability to inhibit β-lactamases, and when a β-lactamase inhibitor is used in combination with a penicillin or cephalosporin it can increase or enhance the antibacterial effectiveness of the penicillin or cephalosporin against certain β30 lactamase producing microorganisms. It is considered that there is an enhancement of antibacterial effectiveness when the antibacterial activity of a combination of a β-lactamase inhibiting substance and a β-lactam antibiotic is significantly greater than the sum of the 5 antibacterial activities of the individual components against β-lactamase producing microorganisms.

The present invention relates to a series of 6βhydroxyalkylpenicillanic acids and esters thereof readily hydrolyzable in vivo which are potent inhibitors of microbial β-lactamases and which enhance the effectiveness of β-lactam antibiotics. The invention further relates to benzyl 6g-hydroxyalkylpenicillanates, said esters being useful chemical intermediates to the corresponding acids.

Pharmaceutical compositions comprising the abovementioned 6B-substituted penicillanic acids and readily hydrolyzable esters thereof with certain β-lactam antibiotics as well as a method for increasing the effectiveness of certain β-lactam antibiotics in combination with the above-mentioned 6B-substituted penicillanic acids and readily hydrolyzable esters thereof are also parts of the present invention.

Di Ninno, et. al., [J. Org. Chem., 42, 2960 (.1977)] have reported the synthesis of 66’-hydroxyalkylpenicillanic acids and the corresponding benzyl esters as potential antibacterial agents and useful intermediates, respectively . 6-Ethylpenicillanic acid and its sulfoxide derivative are claimed as antibiotics in U.S. Patent 4,123,539. 6a-Hydroxypenicillanic acid and esters thereof have been prepared from 6-diazopenicillanic acid and the corresponding esters [J. Org. Chem., 39 1444 (1974)].

U.S. Patent 4,143,046 discloses 6B-substituted sulfonyloxypenicillanic acids as antibacterial agents. 3102G The compounds of this invention are of the formulae and or a pharmaceutically acceptable base salt thereof, wherein R is alkylsulfonyloxymethyl having one to four carbon atoms in the alkyl group, phenylsulfonyloxymethyl or substituted phenylsulfonyloxymethyl(wherein said substitutent is methyl, methoxy, fluoro, chloro, bromo or trifluoromethyl); is benzyl, hydrogen or ester-forming residues readily hydrolyzable in vivo; and R2 is O-R-, I 3 r4-chwherein is alkylsulfonyl of one to four carbon atoms, phenylsulfonyl or substituted phenylsulfonyl (wherein said substituent is methyl, methoxy, fluoro, chloro, bromo or trifluoromethyl); and R^ is hydrogen, alkyl of one to four carbon atoms, phenyl, benzyl, pyridyl or β-phenethyl.

A preferred group of β-lactamase inhibitors are those of formula II wherein and are each hydrogen.

A second group of preferred compounds are those of formula X wherein R^ is hydrogen. Especially preferred within this group are those compounds wherein R is methylsulfonyloxymethyl or £-toluenesulfonyloxymethyl.

The present invention also relates to a pharmaceutical composition useful for treating bacterial infections in mammals, which comprises a pharmaceutically acceptable carrier, a p-lactam antibiotic and a compound selected from the formulae or a pharmaceutically acceptable base salt thereof, wherein R and R are as previously defined and R$ is hydrogen or ester-forming residue readily hydrolyzable in vivo, i.e. in a mammal.

Preferred compounds are those of formulae III and IV wherein R5 is hydrogen or ester-forming residues readily hydrolyzable in vivo selected from alkanoyloxymethyl of three to six carbon atoms, 1-(alkanoyloxy)ethyl of four to seven carbon atoms, 1-methy1-1-(alkanoyloxy)ethyl of five to eight carbon atoms, alkoxycarbonyloxymethyl of three to six carbon atoms, 1-(alkoxycarbonyloxy)ethyl of four to seven carbon atoms, 1-methy1-1-(alkoxycarbonyloxy)ethyl of five to eight carbon atoms, 3-phthalidyl, 4-crotonolactonyl, and y-butyrolacton-4-yl, and said g-lactam antibiotics are selected from penicillins and cephalosporins. Especially preferred are compounds of formula III wherein R is methylsulfonyloxymethyl or p-toluenesulfonyloxymethyl.

The β-lactamase inhibitors of the present invention are conveniently prepared starting with benzyl 6,6-dibromopenicillanate. The condensation of an appropriate aldehyde with the enolate formed through the reaction of benzyl 6,6-dibromopenicillanate with an organometallic reagent, such as the process taught by Di Ninno, et. al., J. Org. Chem., 42, 2960 (1977), results in the formation of a benzyl 6-bromo-6-hydroxyalkylpenicillanate, the initial intermediate leading to the products of the pre10 sent invention.

The product of this initial condensation is comprised of diastereomeric mixtures due to two asymmetric centers, one at the 6-position of the penam nucleus and the second at the carbon atom in the chain at the 6-position, shown as follows: Η As one skilled in the art can readily determine, of these only one is an asymmetric center in this intermediate product when R4 is hydrogen.

The substituents at the 6-position are designated as a or β and are so indicated in the structural formula by a broken or solid bond, respectively. The stereochemical configuration of the substituent in the side chain is designated as (R) or (S) (Cahn, et. al,, Experientia, 12, 81 (1956). The assignment of configuration is based on nuclear-magnetic-resonance spectroscopy.

Experimentally, benzyl 6,6-dibromopenicillanate in a reaction-inert solvent at -20 to -78°C. is treated with about one equivalent of t-butyl lithium or t-butyl magnesium chloride. The resulting enolate is then treated with the appropriate aldehyde and, after a short reaction period, the reaction is quenched and the product isolated by conventional means.

The addition of zinc chloride to a solution of the enolate prior to the addition of aldehyde appears to exert control over the stereochemistry of the condensation product. Accordingly, a high preponderance of CS) configuration in the side chain is obtained under these conditions.

When diethyl zinc is employed as the initial organometallic reagent a preponderance of CR) configuration in the side chain of the product is obtained.

The initial reaction is conducted in an anhydrous reaction-inert solvent, which appreciably solubilizes the reactants without reacting to any great extent with the reactants or products under reaction conditions. It is preferred that said solvents have boiling points and melting points compatible with reaction temperatures.

Such solvents or mixtures thereof include aromatic solvents such as toluene and ethereal solvents such as tetrahydrofuran and diethyl ether.

The molar ratio of the starting penicillanate derivative and the organometallic reagent is not critical to the process. The use of a slight excess of organometallic, up to as much as a ten percent above an equimolar quantity, aids in the completion of the reaction and offers no serious problems in isolating the desired product in purified form.

Moisture can effectively be kept out of the reaction by employing a nitrogen or argon atmosphere.

Reaction time is inherently dependent on concentration, reaction temperature and reactivity of the starting reagents. When the reaction is conducted at the preferred reaction temperature of -60 to -78°C. the reaction time for the formation of the enolate is about 30-45 minutes. The reaction time for the formation of the intermediate product from the aforementioned enolate and aldehyde is about 30-60 minutes.

On completion of the reaction, the product is isolated by conventional means and the diastereomeric mixture can be separated by column chromatography. However, the nature of the next reaction, which is the removal of the 6-bromo substituent, precludes the necessity for said separation of a and 8 epimers at 06.

Treatment of the benzyl 6-bromo-6-hydroxyalkylpenicillanate, resulting from the first reaction, with tri-n-butyltin hydride leads to the formation of a benzyl 6-hydroxyalkylpenicillanate in which the 6-hydroxyalkyl moiety is in the β-configuration. This result is independent of the conformation of the substituents at the 6-position of the starting reagents. Thus 6abromo-6B-hydroxyalkyl esters and 6B-bromo-6a-hydroxyalkyl esters both give, on treatment with tri-n-butyltin hydride, the same δβ-hydroxyalkyl ester as the main product, assuming all other structural parameters in the compounds are the same.

The reaction is carried out in a reaction-inert solvent which appreciably solubilizes the reactants without reacting to any great extent with the reactants or the product under reaction conditions. It is further preferred that said solvent be an aprotic solvent, immiscible with water and have a boiling and freezing point compatible with reaction temperatures. Such solvents or mixtures thereof include the preferred solvents benzene and toluene.

Reaction time is dependent on concentration, reaction temperature and reactivity of the reagents. When the reaction is carried out at the preferred temperature, the reflux temperature of the solvent, the reaction is usually complete in about 4-5 hours.

The molar ratio of the reagents is not critical to the process. Usually an excess of the tin hydride is employed and as much as a 100% excess over an equimolar amount can be employed.

When the reaction is complete the solvent is removed and the residue triturated with hexane to remove the organotin by-product. The intermediate product can be purified and the isomers separated by column chromatography. 510 26 The oxidation of the resulting benzyl 60-(S) and (R)hydroxyalkylpenicillanate to the corresponding sulfones of formula II wherein is benzyl is conveniently carried out using an organic peroxy acid, e.g., a peroxy5 carboxylic acid such as m-chloroperbenzoic acid. The reaction is carried out by treating the appropriate benzyl 6B-(R) or (S)hydroxyalkylpenicillanate with about 2 to about 4 equivalents and preferably about 2.2 equivalents of the oxidant in a reaction-inert solvent. Typical solvents are chlorinated hydrocarbons, such as methylene chloride, chloroform and 1,2-dichloroethane.

The oxidant and substrate are initally combined in a solvent at 0-5°C. The temperature is allowed to rise to room temperature. Reaction time is about 3-6 hours.

During isolation of the sulfones, which are useful intermediates, the solvent is removed and the residue partitioned between water and a water immiscible solvent such as ethyl acetate. The pH of the water-organic solvent mixture is adjusted to 7.0 and any excess peroxide is decomposed with sodium bisulfite. The intermediate product, which is contained in the organic phase, is isolated and purified by conventional means.

The biologically active products of the present invention of formula I and II wherein R^ is hydrogen are pre25 pared by debenzylation of the corresponding benzyl esters. Accordingly, the appropriate benzyl ester is added to a suspension of prehydrogenated 5% palladium-on-calcium carbonate catalyst in a 50% methanol-water solution. The hydrogenolysis is conducted at room temperature and is usually conducted at 45-50 psi pressure. Under these conditions the reaction is usually complete in 30-60 minutes. Filtration of the spent catalyst followed by removal of the solvent by freeze drying results in the isolation of the calcium salt. Acidification of the the filtrate, after removal of the catalyst, followed by extraction with a water immiscible solvent such as ethyl acetate, results in isolation of the free acid wherein Rj is hydrogen.

Alternatively, the compounds of formula II wherein Rx is hydrogen can also be prepared by the same series of reactions previously described, but in a different sequential order. For example, the Initially formed benzyl 6-bromo-6-hydroxyalkylpenicillanates can be oxidized as previously described followed by removal of the 6-bromo substituent with tri-n-butyltin hydride and debenzylation.

The compounds of the present invention are most conveniently prepared by the initial acylation of the requisite benzyl 6β-hydroxyalkylpenicillanate with about an equimolar amount of the appropriate sulfonyl chloride, employing pyridine as the solvent and at a reaction temperature of 0°C. and reaction time of about 2-3 hours. The product is isolated by quenching of the reaction mixture with water followed by extraction and purification.

The second reaction in the series comprises debenzylation of the intermediate ester using hydrogen and 5% palladium-on-calcium carbonate, a procedure previously described.

The final step to compounds of formula II comprises oxidation of the 6B-sulfonyloxyalkylpenicillanic acids with potassium permanganate in a mixture of water-methylene chloride at ambient temperatures at a pH of 6-6.4. Following the reaction, which requires about 45-60 minutes, the pH is adjusted to 1.5 and the product isolated from the organic phase.

When R^ is an ester-forming residue readily hydrolyzable in vivo in a compound of formula I or II it is a group which is notionally derived from an alcohol of the formula R1~OH, such that the moiety COOR.^ in such a compound of formula I or II represents an ester grouping. Moreover, R^ is of such a nature that the grouping COOR^ is readily cleaved in vivo to liberate a free carboxy group (COOH).

That is to say, is a group of the type that when a compound of formula I or II, wherein R^ is an ester-forming residue readily hydrolyzed in vivo, is exposed to mammalian blood or tissue, the compound of formula I or II, wherein R^ is hydrogen, is readily produced. The groups R^ are known in the penicillin art. In most instances they improve the absorption characteristics of the penicillin compound. Additionally, R^ should be of such a nature that it imparts pharmaceuticallyacceptable properties to a compound of formula I or II, and it liberates pharmaceutically-acceptable fragments when cleaved in vivo.

As indicated above, the groups R^ are known and are readily identified by those skilled in the penicillin art, as taught in West German application 2,517,316. Typical groups for are 3-phthalidyl, 4-crotonolactonyl, y-butyrolacton-4-yl, alkanoyloxyalkyl and alkoxycarbonyl25 oxyalkyl. However, preferred groups for are alkanoyloxymethyl having from 3 to 6 carbon atoms, 1-(alkanoyloxy) ethyl having from 4 to 7 carbon atoms, 1-methyl-l(alkanoyloxy)ethyl having from 5 to 8 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxylethyl having from 5 to 8 carbon atoms, 3-phthalidyl, 4crotonolactonyl and y-butyrolacton-4-yl.

Compounds of the formula I or II, wherein R^ is an ester-forming residue readily hydrolyzable in vivo, can be prepared directly from the compound of formula I or II, wherein R^ is hydrogen, by esterification. The specific method chosen will depend naturally upon the precise structure of the ester-forming residue, but an appropriate method will be readily selected by one skilled in the art.

In the case wherein R^ is selected from the group consisting of 3-phthalidyl, 4-crotonolactonyl, y-butyrolacton-4-yl, alkanoyloxyalkyl and alkoxycarbonyloxyalkyl they can be prepared by alkylation of the compound of formula I or II, wherein R^ is hydrogen, with a 3-phthalidyl halide, a 4-crotonolactonyl halide, a y-butyrolacton-4-yl halide, an alkanoyloxyalkyl halide or an alkoxycarbonyloxyalkyl halide. The term halide is intended to mean derivatives of chlorine, bromine and iodine. The reaction is conveniently carried out by dissolving a salt of the compound of formula I or II, wherein R^ is hydrogen, in a suitable polar organic solvent, such as Ν,Ν-dimethylformamide, and then adding about one molar equivalent of the halide. When the reaction has proceeded essentially to completion, the product is isolated hy standard techniques. It is often sufficient simply to dilute the reaction medium with an excess of water, and then extract the product into a water-immiscible organic solvent and then recover same by solvent evaporation. Salts of the starting material which are commonly used are alkali metal salts, such as sodium and potassium salt, and tertiary amine salts, such as triethylamine, N-ethylpiperidine, N,N-dimethylaniline and N-methylmorpholine salts. The reaction is run at a temperature in the range from about 0 to 50°C., and usually at about 0-25C, The length of time needed to reach completion varies according to a variety of factors, such as the concentration of the reactants and the reactivity of the reagents. Thus, when considering the halo compound, the iodide reacts faster than the bromide, which in turn reacts faster than the chloride. In fact, it is sometimes advantageous, when utilizing a chloro compound, to add up to one molar equivalent of an alkali , metal iodide. This has the effect of speeding up the reaction. With full regard for the foregoing factors, reaction times of from 1 to about 24 hours are commonly used.

The compounds of formula I and II, wherein R^ is hydro gen, are acidic and will form salts with basic agents.

Such salts are considered to be within the scope of this invention. These salts can be prepared by standard techniques, such as contacting the acidic and basic components, usually in a 1:1 molar ratio, in an aqueous, nonaqueous or partially aqueous medium, as appropriate.

They are then recovered by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent, or in the case of aqueous solutions, by lyophilization, as appropriate. Basic agents which are suitably employed in salt formation belong to both the organic and inorganic types, and they include ammonia, organic amines, alkali metal hydroxides, carbonates, bicarbonates, hydrides and alkoxides, as well as alkaline earth metal hydroxides, carbonates, hydrides and alkoxides. Representative examples of such bases are primary amines, such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine and octylamine; secondary amines, such as diethylamine, morpholine, pyrrolidine and piperidine; tertiary amines, such as triethylamine, N-ethylpiperidine, N-methylmorpholine and 1,5-diazabi30 cyclo[4.3.0]non-5-ene; hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and barium hydroxide; alkoxides, such as sodium ethoxide and potassium ethoxide; hydrides, such as calcium hydride and sodium hydride; carbonates, such as potassium carbonate and sodium carbonate; bicarbonates, such as sodium bicarbonate and potassium bicarbonate; and alkali metal salts of long-chain fatty acids, such as sodium 2-ethylhexanoate.

Preferred salts of the compounds of formula I and II wherein is hydrogen are the sodium, potassium and triethylamine salts.

As indicated hereinbefore, the compounds of the formula I and II, wherein R^ is hydrogen or an esterforming residue readily hydrolyzable in vivo, are potent inhibitors of microbial β-lactamases, and they increase the antibacterial effectiveness of B-lactam antibiotics (penicillins and cephalosporins) against many microorganisms, particularly those which produce a β-lactamase. The ability of the said compounds of the formula I or II to increase the effectiveness of a βlactam antibiotic can be appreciated by reference to experiments in which the MIC of a given antibiotic alone, and a compound of the formula I or II alone, are measured. These MIC's are then compared with the MIC values obtained with a combination of the given antibiotic and the compound of the formula I or II. When the antibacterial potency of the combination is significantly greater than would have been predicted from the potencies of the individual compounds, this is considered to constitute enhancement of activity.

The MIC values of combinations are measured using the method described by Barry and Sabath in Manual of Clinical Microbiology, edited by Lenette, Spaulding and Truant, 2nd edition, 1974, American Society for Microbiology.

The compounds of the formula I and II, wherein Rj is hydrogen or an ester-forming residue readily hydrolyzable in vivo, enhance the antibacterial effectiveness of 510 26 β-lactam antibiotics in vivo. That is, they lower the amount of the antibiotic which is needed to protect mice against an otherwise lethal inoculum of certain β-lactamase producing bacteria.

The ability of the compounds of formula I and II, wherein R^ is hydrogen or an ester-forming residue readily hydrolyzable in vivo, to enhance the effectiveness of a β-lactam antibiotic against β-lactamase-producing bacteria makes them valuable for co-administration with β-lactam antibiotics in the treatment of bacterial infections in mammals, particularly man. In the treatment of a bacterial infection, the said compound of the formula I or II can be comingled with the β-lactam antibiotic, and the two agents thereby administered simultaneously. Alternatively, the said compound of the formula I or II can be administered as a separate agent during a course of treatment with a β-lactam antibiotic. In some instances it will be advantageous to pre-dose the subject with the compound of the formula I or II before initiating treatment with a β-lactam antibiotic.

When using a compound of formula I or II wherein R^ is hydrogen or an ester group readily hydrolyzable in vivo to enhance the effectivenss of β-lactam antibiotic, a mixture of I or II with the g-laotam antibiotic is administered preferably in formulation with standard pharmaceutical carriers or diluents. A pharmaceutical composition comprising a pharmaceutically-acceptable carrier, a β-lactam antibiotic and a compound of formula I or II wherein R^ is hydrogen or a readily hydrolyzable ester thereof will normally contain from about 5 to about 80 percent of the pharmaceutically acceptable carrier by weight.

When using the compounds of formula I or II wherein is hydrogen or an ester group readily hydrolyzable in vivo in combination with another βτ-lactam antibiotic, said compounds can be administered orally or parenterally, i.e. intramuscularly, subcutaneously or intraperitoneally. Although the prescribing physician will ultimately decide the dosage to be used in a human subject, the ratio of the daily dosages of the compounds of formula I or II and the β-lactam antibiotic will normally be in the range from about 1:3 to 3:1. Additionally, when using the compounds of formula I or II in combination with another β-lactam antibiotic, the daily oral dosage of each component will normally be in the range from about 10 to about 200 mg. per kilogram of body weight and the daily parenteral dosage of each component will normally be about 10 to about 400 mg. per kilogram of body weight. These figures are illustrative only, however, and in some case it may be necessary to use dosages outside these limits.

Typical β-lactam antibiotics with which the compounds of formula I or II and its esters readily hydrolyzable in vivo can be co-administered are: 6-(2-phenylacetamido)penicillanic ac id, 6-(2-phenoxyacetamido)penicillanic acid, 6-(2-phenylpropionamido)penicillanic acid, 6-(D~2-amino-2-phenylacetaraido)penicillanic acid, 6- (D-2-amino-2-[4-hydroxyphenyl]acetamido)penicillanic acid, 6- (D-2-amino-2-[1,4-cyclohexadienyl]acetamido)penicillanic acid, 6- tl-aminocyclohexanecarboxamidolpenicillanic acid, 6- (2-carboxy-2-phenylacetamidolpenicillanic acid, 6- (2-carboxy-2-[3-thienyl]acetamido)penicillanic acid, 6-(D-2-[4-ethylpiperazin-2,3-dione-l-carboxamido]2-phenylacetamido)penicillanic acid, 6-(D-2-[4-hydroxy-l,5-naphthyridine-3-carboxamido]5 2-phenylacetamido)-penicillanic acid, 6-(D-2-sulfo-2-phenylacetamido)penicillanic acid, 6- (D-2-sulfoamino-2-phenylacetamido)penicillanic acid, 6-(D-2-[imidazolidin-2-one-l-carboxamido]-2-phenylacetj0 amido)penicillanic acid, 6-(D-2-[3-methylsulfonylimidazolidin-2-one-l-carboxamidoJ2-phenylacetamido)penicillanic acid, 6-([hexahydro-lH-azepin-l-yl]methyleneamino)penicillanic acid, acetoxymethyl 6-(2-phenylacetamido)penicillanate, acetoxymethyl 6-(D-2-amino-2-phenylacetamido)penicillanate, acetoxymethyl 6-(D-2-amino-2-[4-hydroxyphenyl]acetamido)penicillanate, pivaloyloxymethyl 6-(2-phenylacetamido)penicillanate, 2q pivaloyloxymethyl 6-(D-2-amino-2-phenylacetamido)penicillanate, pivaloyloxymethyl 6-(D-2-amino-2-[4-hydroxyphenyl]acetamido )penicillanate, 1-(ethoxycarbonyloxy)ethyl 6-(2-phenylacetamido)penicil2g lanate, 1-(ethoxycarbonyloxy)ethyl 6-(D-2-amino-2-phenylacetamido)penicillanate, 1-(ethoxycarbonyloxy)ethyl 6-(D-2-amino-2-[4-hydroxyphenyl] acetamido)penicillanate, 30 3-phthalidyl 6-(2-phenylacetamido)penicillanate, 3-phthalidyl 6-(D-2-amino-2-phenylacetamido)penicillanate, 3-phthalidyl 6-(D-2-amino-2-[4-hydroxyphenyl]acetamido)penicillanate, 6-(2-phenoxycarbonyl-2-phenylacetamido)penicillanic acid, 6-(2-tolyloxycarbonyl-2-phenylacetamido)penicillanic acid, 6-(2-[5-indanyloxycarbonyl]-2-phenylacetamido)penicillanic acid, 6-(2-phenoxycarbonyl-2-[3-thienyl]acetamido)penicillanic acid, 6-(2-tolyloxycarbonyl-2-[3-thienyl]acetamido)penicillanic acid, 6-(2-[5-indanyloxycarbonyl]-2-[3-thienyl]acetamido)penicillanic acid, 6- (2,2-dimethyl-5-oxo-4-phenyl-l-imidazolidinyl)penicillanic acid, 7- (2-[2-thienyl]acetamido)cephalosporanic acid, 7-(2-[1-tetrazolyl]acetamido-3-(2-[5-methyl-l,3,4thiadiazolyl]thiomethyl)-3-desacetoxymethylcephalosporanic acid, 7-(D-2-formyloxy-2-phenylacetamido)-3-(5-[1-methyltetrazolyl]thiomethyl)-3-desacetoxymethylcephalosporanic acid, 7-(D-2-amino-2-phenylacetamido)desacetoxycephalosporanic acid, 7-alpha-methoxy-7-(2-[2-thienyl]acetamido)-3-carbamoyloxymethyl-3-desacetoxymethylcephalosporanic acid, 7-(2-cyanoacetamido)cephalosporanic acid, 7-(D-2-hydroxy-2-phenylacetamido)-3-(5-[1-methyltetrazolyl]thiomethyl)-3-desacetoxymethylcephalosporanic acid, 7-(D-2-amino-2-£-hydroxyihe.nylacetamido)desacetoxycephalosporanic acid, 7-(2-[4-pyridylthio]acetamido)cephalosporanic acid, 7-(D-2-amino-2[1,4-cyclohexadienyl]acetamido)cephalosporanic acid, 7-(D-2-amino-2-phenylacetamido)cephalosporanic acid, 7- [D- (.-1 -alpha- (4-ethyl-2,3-dioxo-l-piperazinecarhoxamido) alpha-(4-hydroxyphenyl ]. acetamido] -3-1fl-methyl-1,23,4-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid, 7-(D-2-amino-2-phenylacetamido)-3-chloro-3-cephem-4carboxylic acid, 7-(2-(2-amino-4-thiazolyl)-2-(methoximino)acetamido]cephalosporanic acid, [6R,7R-3-carbamoyloxymethyl-7 C2Z]-2-methoxyimino(fur-2yl!acetamido-ceph-3-em-4-carboxylic acid] 7-(2-(2-aminothiazol-4-yl)acetamido]-3-[([1-2-dimethylaminoethyl)-lH-tetrazol-5-yl]thio)methyl]ceph-3-em4-carboxylic acid, and a pharmaceutically acceptable salts thereof.

As will be appreciated by one skilled in the art, some of the above β-lactam compounds are effective when administered orally or parenteraliy, while others are effective only when administered by the parenteral route.

When compounds of formula I wherein is hydrogen or an ester group readily hydrolyzable in vivo is to be used simultaneously (i.e. co-mingled) with a S-lactam antibiotic which is effective only on parenteral administration, a combination formulation suitable for parenteral use will be required. When the compounds of formula I wherein is hydrogen or an ester group is to be used simultaneously (co-mingled] with a βlactam antibiotic which is effective orally or parenteraliy, combinations suitable for either oral or parenteral administration can be prepared. Additionally, it is possible to administer preparations of the compounds of formula I orally, while at the same time administering a further β-lactam antibiotic parenteraliy; and it is also possible to administer preparations of the compounds of formula I parenterally, while at the same time administering the further β-lactam antibiotic orally.

The following examples are provided solely for 5 the purpose of further illustration. Nuclear magnetic resonance spectra (NMR) were measured at 60 MHz for solutions in deuterochloroform (CDCI2), perdeutero dimethyl sulfoxide (DMSO-dg) or deuterium oxide (DjO) or are noted otherwise, and peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane or sodium 2,2-dimethyl-2-silapentane-5-sulfonate. The following abbreviations for peak shapes are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet.

EXAMPLE 1 6g-41-Tolylsulfonyloxymethylpenicillanic Acid Sulfone A. benzyl 6B-41-tolylsulfonyloxymethylpenicillanate To 1.24 g. of 4-tolylsulfonylehloride in 3.5 ml. °f pyridine cooled to 0°C. and under an argon atmosphere, 800 mg. of benzyl 6B-hydroxymethylpenicillanate in 1.5 ml. of pyridine was added dropwise. After stirring in the cold for 2 hrs., 0.80 ml. of water was added and the stirring continued for 30 min. at 0°C. The reaction mixture was added to 30 ml. of water and the pH adjusted to 1.0 with dilute hydrochloric acid. The agueous was extracted with diethyl ether and the organic phase was separated and washed successively with 1.2N hydrochloric acid, water and a brine solution. The organic layer was dried over magnesium sulfate and evaporated to an oil, 841 mg., which was chromatographed on 100 g. of silica gel using chloroform-ethyl acetate (10:1) as the eluent.

Fractions 10 thru 25 were combined and the solvent removed in vacuo to give 680 mg. of the product. 2q Β. 6β-41-tolylsulfonyloxymethylpenicillanic acid To a suspension of 680 mg. of prereduced 5% palladium-on-calcium carbonate in 20 ml. of methanol-water (1:1) was added 680 mg. of benzyl 6B-4'-tolylsulfonyloxymethylpenicillanate, and the reduction continued at 49 psi for 30 min. An additional 680 mg. of catalyst was added and the reaction continued for an additional 30 min. The catalyst was filtered and the methanol evaporated from the filtrate. The agueous residue was extracted with ethyl acetate and the aqueous layer acidified to pH 2.0. Fresh ethyl acetate was used to extract the acidified aqueous. The organic phase was separated dried over magnesium sulfate and the solvent removed in vacuo to give 463 mg. of the product as a semi-solid.

The NMR spectrum (CDC13) showed absorption at 1.57 (s, 3H), 1.6 (s, 3H), 2.37 (s, 3H), 4.1 (m, 3H) , 4.2 (s, 1H), 5.4 (d, 1H, J=4Hz), and 7.6 (ABq, 4H, J=10Hz) ppm.

C- 6g-4’-tolylsulfonyloxymethylpenicillanic acid sulfone Water (20 ml.) was added to a solution of 460 mg. of 6β-4'-tolylsulfonyloxymethylpenicillanic acid in 20 ml. of methylene chloride and the pH of the resulting mixture adjusted with a sodium hydroxide solution to 6.9. The aqueous layer was separated and the organic layer further extracted with water (2 x 20 ml.). To the combined water layer and washings was added dropwise 238 mg. of potassium permanganate in 5 ml. of water containing 0.16 ml. of phosphoric acid. During the reaction period (45 min.) the pH of the reaction was maintained at 6.0-6.4 by the addition of aqueous sodium hydroxide. The pH of the reaction mixture was then adjusted to 1.5 with 6N hydrochloric acid and 20 ml. of ethyl acetate was added. After cooling the mixture to 0°C., 460 mg. of sodium bisulfite was added in one portion. The pH was readjusted to 1.5 with 6N hydrochloric acid and the organic phase was separated, backwashed with a brine solution and dried over magnesium sulfate. Removal of the solvent gave 300 mg. of the product as a foam.

The NMR spectrum (CDC13) showed absorption at 1.45 (s, 3H), 1.65 (s, 3H), 2.45 (s, 3H), 4.4 (m, 3H), 4.42 (s, 1H), 4.8 (d, 1H, J=4Hz) and 7.6 (ABq, 4H, J=10Hz) ppm.

EXAMPLE 2 Starting with the appropriate sulfonyl chloride and requisite benzyl 6B-hydroxyalkylpenicillanate, and employing the procedures of Example 1 , the following compounds are prepared: CH. r3o-ch *4 CH, co2h —3- —4- — CH3SO2- H- - (CH.,)?CHSO?- H- - ch3(ch2)3so2- H- - CH3SO2- ch3- (S) CH3SO2- (CH3)2CHCH2- (S) CH3CH2SO2-C6H5 (R) CH3SO2- 2'-CgH4N- (S) CH3(CH9)7SO2- 4'-C5H4N- (S) C6H5s°2- CgWa’ (S) c6h5s°2- CH3(CH2)2- (R) C6H5S°2- H- 2-CH3C6H4SO2- H- 4-CH,CfiHdSO?- ch3- (R) 2-CH,CfiH4SO?- CH3(CH2)3- (R) 3-CH3C6h4so2- CgH5(CH2)2- (S) 4-CH3CgH4SO2- 3'-C5H4N- (S) 4-CH3OCgH4SO2- H- ” 4-CH^OCfiH4SO?- (ch3)2ch- (Ξ) 3-CH3OCgH4SO2-C6H5“ (S)2-CH30CeH4S02-C2H5 (R) 4-CH3OCgH4SO2“ 4·-Ο5Η4Ν- (S) 2-FCgH4s°2- H- 4-FCgH4s°2- ch3- (S) 3-FCgH4sO2- (ch3)3c- (R) 4-FCgH4S02- CgH5CH2- (S) 2-FCgH4SO2- 2'-C5H4N- (S) 2-C1C.H.SO,- H- —3- —4- — 2-ClCgH4SO2- (ch3)2chch2- (S) 4-ClCgH4SO2- CgH5CH2- (R) 4-ClCgH4SO2-C6H5(CH2)2- (R) 4-ClCgH4SO2 4'-CsH4N- (S) 2-BrCgH4SO2- H- - 4-BrCgH4SO2- ch3- (R) 4-BrCgH4SO2-C6H5 (S)3-CP3C6H4SO2- H- - 3-CF3cgH4SO2-C2H5~ (R)4-CP3C6H4SO2- H- -4-CP3C6H4SO2- ch3- (S) 4-CF3cgH4s°2-C6H5CH2~ (S) 4-CF3CgH4SO2- 4'-C5H4N- (R) EXAMPLE 3 Acetoxymethyl 6p-£l (RlethylsulfonyloxybenzyjJ_penicillanate Sulfone_ To a solution of 2.22 g. of 6p-Q(Rlethylsulfony5 loxybenzyl]penicillanic acid sulfone sodium salt in ml. of dimethylformamide and cooled to 5°C. is added 648 mg. of chloromethyl acetate. The reaction mixture is allowed to stir at room temperature overnight, and is then poured into water-ethyl acetate. The ethyl acetate layer is separated, backwashed with water and dried over magnesium sulfate. Removal of the solvent in vacuo gives the desired product.

EXAMPLE 4 The procedure of Example 3 is employed, starting with the appropriate 66-sulfonyloxyalkylpenicillanic acid sulfone and halide, to give the following products: R, r. * R-i -3- —4- _ _i- CH3SO2- H- - -CH2O2CCH3 ch,so7- ch3- (S) -CH(CH,)0,C0C,H, CH3CH2SO2C6H5“ (R) -CH2O2COCH3 (CH,),CHSO,- H- - -C(CH,),O,CO(CH,),CH, CH3(CH2)2SO2“4’-C5H4N- (S) -ch2o2cc(ch3)3 CH3(CH2)3SO2- H- - -C(CH3)2O2CC(CH3)3 2-CH-C,-H.SO<3 6 4 2 H- - -C4H3°2a 4-CH.C,H.S093 6 4 2 ch3- (R) -CH2O2CCH(CH3)2 2-CH3OCfiH4SO?-C2H5- (R) -CH(CH3)O2C0CH3 3-CH3OCgH4SO2-C6H5 (S) -CH2O2CCH3 4-CH3OCfiH4SO2- 4'-C5H4N- (S) -CH202CCH3 2-FC6H4SO2- H- - -CH2O2CCH3 4-FC6h4SO2- ch3- (S) -CH,O,CC(CH,), 2-ClCfiH4SO,- (CH,),CHCH,- (S) -C(CH3)2O2CO(CH2)2CH3 4-ClC6H4SO2-C6H5Cii2 (R) -CH2O2CCH3 4-ClC6H4SO2- CgHg(CH,)2~ (R) -CH2O2COCH3 2-BrCfiH4SO,- H- - ~C4H5°2b 4-BrCfiH4SO2- ch3- (R) -C8H5O2<= 3-CF3c6H4SO2- c2h5- (R) -C(CH3)2O2CCH3 4-CF3c6h4s°2 ch3- (S) -CH2O2CO(CH2)2CH3 4-CF3c6h4S°2-C6H5CH2- (S) -CH2O2COCH(CH3)2 c6h5s°2- ch3(ch2)2- (R) -CH2COCH(CH3)2C6H5SO2- h- - -CH2O2CC(CH3)3 C6H5S°2- CgHg(CH,),- (S) -CH(CH3)O2CCH3 a4-crotonolactonyl bY-butyrolacton-4-yl C3-phthalidyl EXAMPLE 5 68-Methylsulfonyloxymethylpenicillanic Acid A. benzyl 68-methylsulfonyloxymethylpenicillanate To a cooled (-10°C.) solution of 800 mg. of benzyl 5 68-hydroxymethylpenicillanate and 0.55 ml. of triethylamine in 25 ml. of methylene chloride was added 194 mg. of methylsulfonyl chloride. After one hour of stirring the reaction mixture was washed successively with water, water at pH 1.0, a saturated sodium bicarbonate solution and a brine solution. The organic phase was dried over magnesium sulfate and evaporated to dryness to give 650 mg. of the desired product.

B. 68-methylsulfonyloxymethylpenicillanic acid To a suspension of 300 mg. of 5% palladium-on-calcium 12 carbonate, prereduced with hydrogen at 47 psi for 15 min., in 20 ml. of methanol-water (1:1) was added 300 mg. of benzyl 68-methylsulfonyloxymethylpenicillanate, and the reduction continued for 30 min at 47 psi. An additional 300 mg. of catalyst was added and the reduction continued for an additional 30 min. The spent catalyst was filtered and the methanol removed in vacuo from the filtrate. The agueous residue was extracted with ethyl acetate and the pH of the aqueous adjusted to 2 with 6N hydrochloric acid. The acidified aqueous was extracted with fresh ethyl ace25 tate and the organic layer separated and backwashed with a saturated brine solution. The organic layer was dried over magnesium sulfate and evaporated to give 269 mg. of the desired product as an oil.

The NMR spectrum (CDClj) showed absorption at 1.56 (s, 3H), 1.68 (s, 3H), 3.06 (s, 3H), 4.1 (m, IH), 4.41 (s, IH), 4.52 (m, 2H), 5.47 (d, IH, J=4Hz) and 8.3 (s, IH) ppm. 5102« EXAMPLE 6 Starting with the appropriate sulfonyl chloride and benzyl 6B-hydroxymethylpenicillanate and employing the procedure of Example 5, the following compounds are prepared: R (ch3)2chso2och2ch3(ch2)3so2och2c6h5s°2och22-CH3C6H4SO2OCH24-CH3OCgH4SO2OCH22-FCgH4SO2OCH22-ClCgH4S020CH22- BrCgH4SO2OCH23- CF3CgH4SO2OCH24- CFoC-H.S0-0CHn3 6 4 2 2 EXAMPLE 7 Pivaloyoxymethyl 68-methylsulfonyloxymethylpenicillanate To a solution of 1.0 g. of δβ-methylsulfonyloxymethyl 5 penicillanic acid sodium salt in 10 ml. of dimethylformamide cooled to 0-5°C. is added 0.53 ml. of chloromethyl pivalate, and the resulting reaction mixture allowed to stir at room temperature overnight. The mixture is poured into water-ethyl acetate, and the organic layer separated, backwashed with a brine solution and dried over magnesium sulfate. Removal of the solvent in vacuo gives the desired product.

EXAMPLE 8 Starting with the appropriate penicillanic acid and requisite halide, and employing the procedure of Example 7, the following compounds are prepared: — £l- CII3GO2OCH2- -CH(CH3)O2CCH3 CH3SO2OCH2- -CH2O2CCH3 CH3SO2OCH2- -CH2O2COCH(CH3) (CHj)2CHSO2OCH2- -CH2O2CCH3 (CH3)2CHSO2OCH2- -CH2O2COCH3 (CH3)2CHSO2OCH2- “C4H3°2a (CH3)2CHSO2OCH2- -C(CH3)2O2CC(CH3)3 CH3(CH2)3SO2OCH2- -CH(CH3)O2CO(CH2)3CH3 CH3(CH2)3SO2OCH2- -CH2O2CCH3 CH3(CH2)3SO2OCH2-C4H5°2b c6h5so2och2- -CH(CH3)O2COC2H5 c6h5so2och2- -CH2O2C(CH2)4CH3 2-CH3CgH4SO2OCH2- -CH2O2CC(CH3)3 2-CH3CgH4SO2OCH2- -CH(CH3)O2CCH3 2-CH3CgH4SO2OCH2- -CH(CH3)O2COC2H5 4-CH3OCgH4SO2OCH2- -C8H5°2G 4-CH3OCgH4SO2OCH2- -ch2o2cch3 4-CH3OCgH4SO2OCH2- -CH2O2OCC(CH3)3 4-CH3OCgH4SO2OCH2- -CH(CH3)O2COC2H5 2-FCcH.S0Q0CHo6 4 2 2 “C4H3°2a 2-FCgH4SO2OCH2- -CH2O2C(CH2)4CH3 2-FCgH4SO2OCH2- -C(CH3)2O2CO(ch2)2CH3 2-ClCgH4SO2OCH2- -CH2O2COCH(CH3)2 2-ClCgH4SO2OCH2- -ch2o2cch3 2-ClCgH4SO2OCH2- -CH(CH3)O2COC2H5 2-ClCgH4SO2OCH2- -C4H3°2a 2-BrCgH4SO2OCH2- -C4H5°2b 2-BrCgH4SO2OCH2- -CH2°2CCH3 2-BrCgH4SO2OCH2- -CH2O2COCH3 3-CF3CgH4SO2OCH2- -CH2O2CC(CH3) 3 3-CF,C,H,SO„OCH_3 6 4 2 2 -C.Hco_b 4 5 2 4-CF3CgH4SO2OCH2- -C(CH3)2O2CC(CH3)3 4-CF3CgH4SO2OCH2- -CH2O2CCH3 4-CF3CgH4SO2OCH2- -CH(CH3)O2CO(CH2)3CH3

Claims (8)

CLAIMS A compound of the formula:

1. or a pharmaceutically acceptable base salt thereof, 5 wherein R is alkyl-sulfonyloxymethyl having one to four carbon atoms in the alkyl group, phenylsulfonyloxymethyl or substituted phenylsulfonyloxymethyl (wherein said substituent is methyl, methoxy, fluoro, chloro, bromo or trifluoromethyl); R^s benzyl, hydrogen 10 or an ester-forming residue readily hydrolyzable in vivo; R 2 is I r 4 -chwherein is alkylsulfonyl having from one to four carbon atoms, phenylsulfonyl or substituted phenylsulfonyl (wherein 15 said substituent is methyl, methoxy, fluoro, chloro, bromo or trifluoro-methyl); and R 4 is hydrogen, alkyl having one to four carbon atoms, phenyl, pyridyl, benzyl or p-phenethyl.

2. A compound of claim 1, Formula II, wherein R^ 20 is hydrogen.

3. A compound of claim 2, wherein R 4 is hydrogen.

4. 6-(3-(Methylsulfonyloxymethyl)penicillanic acid.

5. 6-(3-(p-Toluenesulfonyloxymethyl)penicillanic acid.

6. A pharmaceutical comfwsltion useful for treating bacterial infections in mammals, which comprises a pharmaceutically acceptable carrier, a p-lactam antibiotic and a compound as claimed in any preceding claim, 5 with the proviso that R is not benzyl.

7. A pharmaceutical composition of claim 6, wherein is hydrogen, alkanoyloxymethyl of three to six carbon atoms, 1-(alkanoyloxy)ethyl of four to seven carbon atoms, 1-methyl-1-(alkanoyloxy) ethyl of five to eight carbon

8. 10 atoms, alkoxycarbonyloxymethyl of three to six carbon atoms, 1-(alkoxycarbonyloxy)ethyl of four to seven carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl of five to eight carbon atoms, 3-phthalidyl, 4-crotonolactonyl or Y-butyrolacton-4-yl.